The emergence of epidemic arboviral diseases infecting both humans and domestic animals has led to significant world-wide morbidity and mortality. Little is known about the host factors required for the replication cycles of these viruses, and less about the innate immune pathways that restrict pathogenesis, impeding the development of antiviral treatments. The identification of cellular factors involved in viral replication and pathogenesis has been difficult due to the lack of virus-host systems amenable to genetic screening. Our primary research goal is to use a high-throughput RNAi and small molecule screens in Drosophila and mammalian cells to identify inhibitors of both cellular and viral factors that regulate pathogenesis, including both those factors hijacked by the virus for replication, and those systems used by the host to combat the viral invader. Our studies will be focused on Rift Valley Fever Virus (RVFV, a Category A bunyavirus), but will be extended via collaborations within MARGE to other bunyaviruses of medical significance. RVFV is of particular interest due to its unmet medical and agricultural need, its identification by the USDA as a likely agroterrorism agent, the availability of reagents and experimental systems, and because of the opportunity to collaborate with members of the MARCE. Our cell-based screening approach using replication competent virus enables the identification of compounds or genes that target any factorviral or cellularthat is required for viral replication. Furthermore, our method has the ability to elucidate the mechanism of this requirement by dissecting viral replication with secondary assays against each step in the lifecycle. The simultaneous application of genome-scale RNAi screens against RVFV and small molecule screens, both using a 384 well plate-based high throughput screening assay (HTS) that we have developed, should lead to more rapid identification of cellular targets for antiviral drug development for this medically important virus, as well as for other members of this under-studied virus family.